In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. The central aim is to identify approaches that will result in a net therapeutic gain, thus improving cancer treatment with radiation. One goal of the project is to define and better understand those aspects of tumor physiology, including cellular and molecular processes and the influence of the tumor microenvironment on treatment response. The ability to enhance the response of the tumor to radiation, without enhancing normal tissue within a given treatment field is desirable. We are in the final stages of completing a pre-clinical study of a novel HSP90 inhibitor as a radiation sensitizer (in vitro and in vivo). Significant in vitro radiation dose modification factors have been observed with this agent and xenograft studies indicate that the combination of the drug with fractionated radiation results in enhanced radiosensitivity. Further we have identified molecular biomarkers that will be helpful in assessing treatment efficacy. This agent also has potential of being translated into human clinical trials. We are near completion of another prec-clinical study a CDK4/6 inhibitor, which demonstrates significant radiosensitization in vitro and in vivo. We continue to evaluate a number of metabolic inhibitors as radiation modifiers under the working hypothesis that inhibition of metabolism (for example, decreased ATP production) will diminish the repair of radiation-induced DNA damage. We have preliminary in vitro data indicating that a novel lactate dehydrogenase inhibitor enhances the radiosensitivity of human pancreatic carcinoma cells, xenograft studies are in progress. These pre-clinical studies will provide the necessary information to consider all three of these agents in a clinical human trial for tumor radiosensitization. With respect to normal tissue response to radiation, a publication has been accepted demonstrating that rapamycin supplied in the animal's chow protects against radiation-induced lung fibrosis in part by preventing radiation induced stem cell senescence. We continue to develop a test novel functional imaging platforms to better understand the contribution of tumor hypoxia and metabolism on radiation and drug induced tumor response in tumor-bearing animals. Collectively, we have identified a number of pre-clinical approaches to initiate human radiation oncology clinical trials for modulation of radiation effects on tumors and normal tissues.